“This application claims priority to U.S. Provisional Patent Application Ser. No. 60/535,990, entitled “RIFAMYCIN DERIVATIVES EFFECTIVE AGAINST DRUG-RESISTANT MICROBES” filed on Jan. 13, 2004, having Zhenkun Ma, Yafei Jin, Jing Li, Charles Z. Ding, Keith P. Minor, Jamie C. Longgood, and Timothy W. Morris, listed as the inventors, the entire content of which is hereby incorporated by reference.”
This invention relates to a compound of rifamycin derivative having antimicrobial activities, its compositions, and methods for treatment and prevention of microbial infections. More particularly, the rifamycin derivative of the current invention is a rifanycin moiety covalently linked to a linker through the C-3 carbon of the rifamycin moiety and the linker is, in turn, covalently linked to a therapeutic moiety or antibacterial agent or pharmacophore. The inventive rifamycin derivatives are active against drug-resistant microorganisms with reduced frequency of developing mutational resistance in the microorganisms.
Rifamycins are natural products with potent antimicrobial activity. Examples of the naturally-occurring rifamycins are rifamycin B, rifamycin O, rifamycin R, rifamycin U, rifamycin S, rifamycin SV and rifamycin Y (Brufani, M., Cerrini, S., Fedeli, W., Vaciago, A. J. Mol. Biol. 1974, 87, 409-435). The therapeutic applications of the naturally-occurring rifamycins are limited due to their poor oral bioavailability, weak activity against Gram-negative pathogens and low distribution into the infected tissues. Significant efforts have been made toward identifying semi-synthetic rifamycin derivatives to address the deficiencies. As a result, many semi-synthetic rifamycin derivatives with improved spectrums and pharmacological profiles have been identified. Among the semi-synthetic compounds, rifampin, rifabutin and rifapetine have been developed into therapeutic agents and are widely used for the treatment of tuberculosis and other microbial infections (Farr, B. M. Rifamycins, in Principles and Practice of Infectious Diseases; Mandell, G. L., Bennett, J. E., Dolin, R., Eds.; Churchhill Livingstone: Philadelphia; p348-361).
At present, one of the major problems associated with the rifamycin class of antimicrobial agents is the rapid development of microbial resistance. Mutations in RNA polymerase are mainly responsible for the high frequency of microbial resistance to rifamycins. Consequently, rifamycins are currently used only in combination therapies with other antibiotics to minimize the development of resistance to this class of drug. Compounds of the current invention are designed to address the rifamycin resistance problem by covalently attaching another antibiotic pharmacophore to the C-3 position of the rifamycin molecules. The resulting rifamycin compounds of this invention exert their antimicrobial activity through dual or triple antibacterial mechanisms and therefore they exhibit reduced frequency of resistance.
Reference is made to U.S. Pat. No. 5,786,350 that discloses a series of C-36 derivatives of rifamycins, including derivatives formed by linking the C-3 carboxy group of a fluoroquinolone to the C-36 position of rifamycins through a chemically or metabolically labile ester group to deliver rifamycin and quinolone separately in vivo.
Reference is also made to PCT application WO 03/045319 A2 that discloses rifamycin derivatives formed by linking rifamycin and a therapeutic drug or antibacterial agent and the use of these derivatives as vehicles or pro-drugs for delivering the therapeutic drugs or antibacterial agents separately. However, this reference failed to demonstrate by specific examples that any drug is introduced to the C-3 position of a rifamycin molecule.